Benzodiazepine derivatives

ABSTRACT

Benzodiazepine compounds of the formula   WHEREIN R1 is hydrogen or a hydrocarbon residue, R2 is hydrogen or a lower alkyl group, the rings A and B are unsubstituted or substituted by one or more of nitro, trifluoromethyl, halogen, alkyl and alkoxy groups are produced by reacting a compound of the formula WITH A REACTIVE DERIVATIVE OF A CARBOXYLIC ACID TO PRODUCE A COMPOUND OF THE FORMULA   WHEREIN -OCOR3 is an acyloxy group convertible to a hydroxy or alkoxy group AND SUBJECTING COMPOUNDS II to hydrolysis or alcoholysis and optionally subjecting the compounds I wherein R2 is hydrogen to etherification. Compounds I and II are useful as anticonvulsants, sedatives and tranquilizing agents.

United States Patent [1 1 Meguro et al.

[ Sept. 23, 1975 BENZODIAZEPINE DERIVATIVES [75] Inventors: Kanji Meguro, Nishinomiya; Yutaka Kuwada, Ashiya, both of Japan [73] Assignee: Takeda Chemical Industries, Ltd.,

Japan [22] Filed: Mar. 5, 1970 [21] App]. No.: 16,970

[30] Foreign Application Priority Data Primary ExaminerAlton D. Rollins Attorney, Agent, or Firm-Wenderoth, Lind & Ponack [57] ABSTRACT Benzodiazepine compounds of the formula wherein R is hydrogen or a hydrocarbon residue, R is hydrogen or a lower alkyl group, the rings A and B are unsubstituted or substituted by one or more of nitro, trifluoromethyl, halogen, alkyl and alkoxy groups are produced by reacting a compound of the formula with a reactive derivative of a carboxylic acid to produce a compound of the formula )wherein OCOR is an acyloxy group convertible to a hydroxy or alkoxy group and subjecting compounds [I to hydrolysis or alcoholysis and optionally subjecting the compounds I wherein R is hydrogen to etherification. Compounds l and II are useful as anticonvulsants, sedatives and tranquilizing agents.

12 Claims, No Drawings 1, BENZODIAZEPINE DERIVATIVES This invention relates to novel and useful'bcnzodiazepine derivatives of the general formula (I) wherein R is hydrogen or a hydrocarbon residue, R is hydrogen or lower alkyl, the rings A and B areunsubsti tuted or substituted by one or more of hitr'o, triflu or omethyl, halogen, alkyl and alkoxy groups,'which can be the same or different, and also relates to a novel and useful process for producing the benzodiazepine deriv- The present invention is further concerned with novel and useful intermediates of the following general formula (ll) for the production of the benzodiazepine derivatives (1) and with a novel and useful process for the production of the intermediates;

N N N wherein -OCQR,-, is an acyloxy group convertible to hydroxy or alkoxy group, and the other symbols have the same meanings as given above.

The object benzodiazepine derivatives (I) of the present invention are useful, for example, as anticonvulsants, sedatives and tranquilizing agents without causing undesirable side effects.

Referring to the general formula (I), as the hydrocarbon residue represented by R there are generally mentioned those having I to 8 carbon atoms, which includealkyl of up to 6 carbon atoms (cg, methyl, ethyl, propyl. isopropyl. butyl, secbutyl, terit-butyl. amyl and hexyl), aralkyl (cg: ben zyl and phenethyl) and aryl (e.g. phenyl). The lower alkyl of is that having lJto 4 carbon atoms which is exemplified by methyl -ethyl, prop yl, isopropy hbutyl, tcrt-butyl, etc. The rings A and B are unsubstituted or substituted by one or, more substituents, which are the same or different, selected from nitro, triflu oromethyl halogen (i.e. chlorine, fluorine, bromine and iodine), alkyl such as-lower alkyl (cgv methyl, ethyl and propyl-land alkoxy such as lower alkoxy (e.g. mcthoxy and ethoxy). i

The benzodiazepine derivatives (I) of the present invention can be produced by allowing compounds of the general formula, (Ill) (III) wherein allthesymbols have the same meanings as given above, toreact with reactive derivatives (IV) of carboxylic acids, the carboxylic acid being represented bythe general formula R COOH, whereby the intermediates (II) are produced, and then subjecting the intermediates :(II) to hydrolysis or to alcoholysis, and optionally subjecting the benzodiazepine derivatives (1), wherein R is hydrogcn, to etherification.

The reactions ofthe present invention are summa-.

rized asin the following scheme:

, etherification (Step 4) The above stepsH 'to- (4). detail as follows:

According to the step (-1 o f the. present invention, the compounds lll) are allowed to react with the reactive derivatives (lV) of carboxylic acids. The com-" box ylic acid of the general formula R;,COOH include acetic acid, propionic acid, butyric acid, benzoic acid, phcnylacetic acid, etc.

The reactive derivatives of the carboxylic acid, which are employed in this method, in'clude'acid anhydrides, acid halides (e.g., acid chlorides, acid bromides, etc.) and acid sulfides.

The present reaction ofthe step l') is gcnerally'con ducted by allowing the reactive derivatives (IV) of carboxylic acids to react with the compound (Ill') in the presence of a suitable solvent with or without-heating.

The reactive derivatives (IV) of the carbox yli'c acid may act as a solvent, when they-are in a liquid state. Amount of the reactive derivatives (IV) is about 2' to 5 moles per mole of the compound (Ill).

Thus produced intermediates (II) are subjected to the step (2) or the step (3) of the present invention with or without isolating them from the'reaction mixture. The isolation of the intermediates is conveniently conducted, for example, by evaporating the solvent from the reaction *mixture. The intermediates (ll may be obtained in the form of suitable acid salts (e.g., hydrochloride), and for purposes of this invention said salts are the equivalents of the free compounds.

According to the step (2) of the present invention, the intermediates (ll) are subjected to hydrolysis. The intermediates (ll) may be used in the form of suitable acid salts. The hydrolysis is generally conducted in the presence of alkali (e.g., sodium hydroxide, potassium hydroxide, etc.) in a suitable solvent at room temperature. The reaction can be controlled by suitable cooling or heating, if necessary. In the present step (2) benzodiazepine derivatives (I), wherein R is hydrogen, are produced and are conveniently separated, for example, by evaporating the solvent from the reaction mixture. The benzodiazepine derivatives (I) may be obtained in the form of a suitable acid salt (e.g. hydrochloride) by conventional means. i

According to the step (3) of the present invention,- the intermediates (II) are subjected to alcoholysis. The intermediates (ll) may be employed in the form of an acid salt. The alcoholysis is generally conducted by allowing the intermediates (ll) to react with alcohols (c.g. methanol, ethanol, propanol, isopropanol, butanol, tcrt-butanol, etc.) suitable for introduction of the desired alkoxy groups in the presence of acids (e.g., hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, p-toluenesulfonic acid, etc.) in suitable solvents (e.g., chloroform, carbon tetrachloride, etc.) in a suitable temperature range between room temperature and the boiling point of-the solvent used. The alcohol may act as the solvent. Thusproduce d benzodiazepine derivatives (l) wherein R is lower alkyl, are conveniently will he-explained in more separated, for example, by evaporating the solvent from the reaction mixtures. The benzodiazepine derivatives (I) may be obtained in the form of acid salts which are the equivalents of the free compounds.

According to the step (4) of the present invention, the benzodiazepine derivatives (I) wherein R is hydrogen, are subjected to etherification. The etherification is generally conducted by allowing the benzodiazepine derivatives (1) wherein R is hydrogen, to react with an alcohol which is suitable for introduction of the desired alkoxy groups, in the presence of suitable solvents (e.g. chloroform, carbon tetrachloride, etc.) in a temperature range between room temperature and the boiling point of the solvent used. This reaction is conducted preferably in the presence of acids (e.g. hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, p-toluenesulfonic acid, etc.). The benzodiazepine derivatives (I) may be employed in the form of acid salts. The alcohol used for the ethcrification may act as the solvent. Thus produced benzodiazepine derivatives (I) wherein R is lower alkyl, are conveniently separated, for example, by evaporating the solvent from the reaction. mixture. The benzodiazepine derivatives (I) wherein R; islower alkyhmay be obtained in the form ofsuitable acid salts (e.g. hydrochlorides).

The starting compounds (III) which are employable in the present invention can be prepared, for example, by allowing the compounds of the general formula (V) (NH-NH are produced, and then by allowing the thus produced compounds (Vl) to react with orthoesters of the general formula R C (0R wherein R, has the same N'HNl-ICOR (VII) are. produced, and then by subjecting the thus produced compounds (V1l)'to cyclization.

The above two reactions for the production of the starting compounds ([11) are schematically represented as follows:

benzodiazepine derivatives (I) or their acid salts to beadministered varies depending on the kinds of the compoundspthe severity of the disease, etc., but generally falls within the range of from about 1 to about milligrams for oral administration, and about 0.5 to about 10 milligrams for parenteral administration for an adult human per day.

The compounds (11) are useful not only as intermediates for the production of the benzodiazepine derivatives (l) of the present invention, but also as medicines producing medicinal effects similar to those of the henzodiazepine derivatives (1) of the present invention.

For further detailed explanation of the present invention', the following references and examples are given, wherein the term part(s) means weight part(s)" unless otherwise specified. and the relationship between part( s) andpart(s) by volurrie corresponds to that between gram(s) and milliliter(s).

REFERENCE 1 To a mixture of 3 parts of 2amino-7-nitro-5-phenyl- 3H-1 4-benzodiazepine 4N-oxide and parts by volume of ethanol are added 2.5 parts by volume of 100% hydrazine hydrate and 1.8 parts by volume of acetic acid. The whole mixture is slightly warmed on a water bath for a while to result in a solution and stirred at room temperature for about 20 minutes. The precipitated crystals are collected, and washed with ethanol and then with diethyl ether, whereby 2-hydrazino-7- nitro-5phenyl-3H-1,4-benzodiazepine 4H-oxide is yielded as yellow needles melting at 176C (sintering), 226C (decomposition).

Elemental analysis C H N O Calculated: C 57.87,

H 4.21, N 22.50; Found: C 57.98, H 4.01, N 22.26.

To a suspension of 1.55 parts of 2-hydrazino-7-nitro- 5-phenyl-3H- l ,4- benzodiazepine 4N-oxide in 100 parts by volume of ethanol is added 3.7 parts of ethyl orthoformate, and then 0.6 part by volume of concentrated sulfuric acid, whereby the solid substance is dissolved and then yellow crystals are precipitated. After stirring for 30 minutes, the mixture is neutralized with a saturated aqueous solution of sodium bicarbonate. The crystals are collected and washed with water, ethanol and then diethyl ether, whereby 8-nitro-6-phenyl-4H-striazolo [4,3-a][ l,4]-benzodiazepine SN-oxide is yielded as yellow crystals. Recrystallization from an aqueous dimethylformamide yields yellow crystals melting at 274C to 275C (decomposition).

Elemental analysis: C H N O Calculated: C 59.81, H 3.45, N 21.80; Found: C 59.58, H 3.48, N 21.56.

REFERENCE 2 To a suspension of 14.3 parts of 2-amino-7-chloro-5- phenyl-SH-1,4-benzodiazepine 4N-oxide in 400 parts by volume of methanol are added 12.5 parts by volume of 100% hydrazine hydrate and 10 parts by volume of methanol saturated with hydrogen chloride. The mixture is refluxed for 10 minutes and the resulting solution is concentrated to half the initial volume. The concentrate is poured into 500 parts by volume of water and the resulting oily substance is extracted with chloreform. The chloroform layer is dried over sodium sulfate and evaporated. Treatment of the residue with diethyl ether gives 7-chloro-2-hydrazino-5-phenyl-3H- l,4-benzodiazepine 4N-oxide as pale yellow powdery crystals melting at 262C to 263C.

Elemental analysis: C -,H ;,ClN,O; Calculated: C 59.90, H 4.36, N 18.63; Found: C 60.05, H 4.13, N 18.41.

To a mixture of 1.5 parts of 7-chloro-2-hydrazino-5'- phenyl3Hl,4- benzodiazepine 4N-oxide, 50 parts by volume of tetrahydrofuran and 1 part by volume of triethylamine is added 0.5 part by volume of acetic anhydride with stirring. The whole mixture is stirred for about 1 hour. followed by the addition of water, whereby 2-(Z-acetylhydrazino)-7-chloro-5-phcnyl-3H 1,4-benzodiazepine 4N-oxide is yielded as'crystals. Re crystallization from a mixture of dimethylformamide and water yields fine needles melting at 256C to 8C (decomposition). v

Elemental analysis: C H CIN O Calculated: C 59.56. H 4.41, N 16.35; Found: C 59.38. H 4.55, N 16.30.

A mixture of 3.4 parts of 2-(2-acetylhydrazino)-7- chloro-5-phenyl-3H-l,4-benzodiazepine 4N-oxide, and parts by volume of pyridine is refluxed for 4 hours,

followed by evaporation of the pyridine under reduced pressure. The rsidue is recrystallized from methanol,

8-chloro-lmethyl-6-phenyl-4Hs- 1 whereby triazolo[4,3-a][1,4j-benzodiazepine 5N-oxide is yielded as needles melting at 272C to 274C (decomposition).

Elemental analysis: C H ClN O; Calculated: C

62.87, H 4.03, N 17.25; Found: C 63.04, H 4.04, N

17.26. Any other starting compounds can also be prepared in a similar manner to the above References.

EXAMPLE 1 A mixture of 1.5 parts of 8-chloro- 6phenyl-4H-striazolo[4,3-a][1.4]benzodiazepine 5-N-oxide and 50 parts by volume of acetic anhydride is heated at 90C for 1.5 hours, followed by evaporation of the solvent under reduced pressure. The residue is treated with diethyl ether, whereby 4-acetoxy-8-chloro-6-phenyl{4H- S-triazo1o[4,3-a][l,4]-benzodiazepine is yielded as crystals. Recrystallization from methanol yields colorless needles melting at 232 to 233C.

Elemental analysis: C H ClN O Calculated: C 61.28, H 3.71, N 15.88; Found: c 61.56, H, 3.72, N 15.95.

EXAMPLE 2 EXAMPLE 3 A mixture of 3.25 parts of 8-ch1oro-l-methyl6- phenyl-4H-s-triazolo[4,3a][ 1,4]benzodiazepine SN- oxide and 60.parts iby volume of acetic anhydride is heated at C for 2 hours, followed by evaporation of the solvent under reducedpressure. The residue is treated with diethyl ether, whereby 4-acetoxy-8- chlorol -methyl-6-phenyl-4H-striazolo[ 4,3- a][ 1,4]benzodiazepine is yielded as crystals. Recrystallization from a mixture of methanol and petroleum ether yields colorless needles melting at 229 to 230C (decomposition).

Elemental analysis: C ,,H ClN O Calculated: C 62.21, H 4.12,'N 15.28; Found: C 62.23. H 3,83,181 15.42.

EXAMPLE 4 A mixture of 3.3 parts of 8-chloro-1-ethyl-6-phenyl- 4H-s-triazo1o[4,3-all 1,4]benzodiazepine SN-oxide and parts by volume of acetic anhydride is heated at 90C for 2.5 hours. The solvent is removed by distillation under reduced pressure and water is added to the residue, whereby 4-acetoxy-8chloro'1-ethyl-6-phenyl-' 4H-s-triazolo[4,3-a][1,4]benzodiazepine is yielded as an oil.- The oil is extracted with chloroform and the chloroform and the chloroform layer is washed with water and dried. After'evaporation of the solvent, the residue is dissolved in 50 parts by volume of ethanol, followed by the addition of 5 parts by volume of 4N aqueous sodium hydroxide solution. The mixture is left standing at room temperature for 30 minutes and acidifiedby the addition of acetic acid. Thesolvent is evaporated and the residue is treated with an aqueous ethanol, whereby 8-chloro-l-ethyl-4-hydroxy-6-phenyl-4H s-triazo1o[4,3-a][l,4] -benzodiazepine is yielded as crystals. Recrystallization from methanol yields colorless prisms melting at 254 to 255C.

Elemental analysis: C,,,H,,-,C1N ,O; Calculated: C 63.81, H 4.46, N 16.54; Found: C 63.97, H 4.58, N 16.61. 1

1 EXAMPLE '5 A suspension of 3 .2 parts of 8- nitr0-6 -phenyl-4H-striaz olo[4,3-a] [1,4]be nzodiazepine 5N-oxide in .100 partsby yolti rne'o f acetic anhydride is heated at 90C for 3 hours, followed by evaporation of the solvent. Treatment of their'esiduewith diethyl ether gives 4- acetoxy-8-nitro-6 phenyl-4H-s-triazolo[4,3 a] 1,4]be'nzodiazepine as I crystals. Recrystallization from a mixture of tetrahydrofuran and diethyl ether gives colorless prisms melting at 253 .to 254C (decomposition). v v

Elemental analysis: C H N Q Calculated: C 59.50, H 3.61,'N 19.28; Found: c $944,113. 2, N 13.99.

EXAMPLE'6 A A mixture of 3.53 parts of 4-ae'etoxy-8-chlo ro-6- phenyl-4H-s-triazolo[4,3-a][ 1,4]benzodiazepine, 50 parts byvolume of ethanol and 6 parts by volume of 4N aqueous sod'ium hydroxide solution is. left standing at room temperature for 30 minutesdfollo'wed by acidifi cation with acetic acid. The solvent is evaporated from the mixture under reduced pressure and water is added to the residue, whereby 8-ehloro-4 hydroxy-6ph enyl- 4H-s triaz'olol 4,3-a][ 1,4]benzodiazepine is yielded as crystals Recrystallization from methanol yields colorless pris'nisrnelting at 24l to 242C.

Elcmen'talhanalysis: C1 H,"{ClN O; Calculated: C 61.84, H"'3.-57;'N 18.03; Found: C 61.77, 3.45, N 17.81. 1

EXAMPLE 7 a][ 1,4]ben zodiazepine in 100 parts by volume of ethanol is added 6 parts by volume ofAN aqueous sodium hydroxide solution. After stirring the mixture for about minutes, the resulting solution is acidif ed with acetic acid. Evaporation of the solvent andfthen addition of water to the residue affords 8-chloro 4-hydroxyl-methyl-6-phenyl-4H-s-triazolo[4,3- a][ l ,4]benzodiazepine as crystals. Recrystallization from a mixture of dimethylformamide and water yields its hemihydrate as colorless needles melting at 245.5C (decomposition).

Elemental analysis: C H, ClN O l/2H O; Calculated: C 61.17, H 4.22, N 16.79; Found: C 61.06, H 4.37, N 16.87.

EXAMPLE 8 To a suspension of 1.2 parts of 4-acetoxy-8-nitro-6- phenyl-4H-s-triazolol4,3-a][ 1,4]benzodiazepine in 15 parts by volume of ethanol is added 6.6 parts by volume of 1N aqueous sodium hydroxide solution, and the mixture is left standing at room temperature for about 10 minutes. The resulting solution is acidified with acetic acid. whereby 4-hydroxy-8-nitro-6-phenyl-4H-striazolo[4,3-a][ l ,4]-benzodiazcpine is yielded as crystals. Recrystallization from aqueous dimethylformamide yields yellow crystals melting at 236.5C (decomposition).

Elemental analysis: C H N O Calculated: C 59.81, H 3.45, N 21.80; Found: C 59.45, H 3.70, N 21.77.

EXAMPLE 9 To a suspension of 1.5 parts of 8-chloro-4-hydroxy-6- phenyl-4H-s-triazolo[4,3-a]l 1,4]bcnzodiazepine in 100 parts by volume of methanol is added 0.5 part by volume of glacialacetic acid, and then the mixture is refluxed for 3.5 hours. Evaporation of the solvent yields 8-chloro-4-methoxy-6-phenyl-4H-s-triazolo[4,3- all 1,4]benzodiazepine as colorless crystals. Recrystallization from methanol yields colorless needles melting at 270 to 271C (decomposition).

Elemental analysis: C H CIN O; Calculated: C 62.87, H 4.03, N 17.25; Found: C 63.06, H 3.88, N

EXAMPLE 10 wherein R is hydrogen or alkyl of up to 6 carbon atoms, R; is hydrogen or lower alkyl, the rings A and B are unsubstituted or substituted by one member se lected from the group consisting of nitro, trifluoromethyl, halogen, lower alkyl and lower alkoxy, which can be the same or different, and pharmaceutically acceptable acid salts thereof.

2. A compound according to claim 1, said compound being 8-chloro-4-hydroxy-6-phenyl-4H-s-triazolo-[4,3 a][ [,4]benzodiazepine.

3. A compound according to claim 1, said compound being 8-chloro-4-hydroxyl -methyl-6-phenyl-4H-striazolo[4,3a][ l ,4]benzodiazepine.

4. A compound according to claim 1, said compound being 8-chlorol -ethyl-4hydroxy-6-phenyl-4H-striazolo[4,3-a][ 1,4benzodiazepine.

5. A compound according to claim 1, said compound being 4-hydroxy-8-nitro-6-phenyl-4H-s-triazo1o-[4,3- a][ 1,4]benzodiazepine.

6. A compound according to claim 1, said compound being 8-chloro-4-methoxy-6-phenyl-4H-s-triazolo- [4,3-a][ 1,4]benzodiazepine.

7. A compound selected from the group consisting of a compound of the formula A OCOR. 3

wherein R, is hydrogen or alkyl of up to 6 carbon atoms, R, is alkyl of l4 carbon atoms and the rings A and B are unsubstituted or substituted by one member selected from the group consisting of nitro, trifluoromethyl, halogen, lower alkyl and lower alkoxy, which can be the same or different, and acid salts thereof.

8. A compound of the formula l l 12 wherein R is hydrogen or alkyl of up to 6 carbon l0. A compound according to claim 7, said comatoms, R is hydrogen, methyl, ethyl, propyl, isopropyl, pound being 4-acetoxy-8-chloro-l-methyl-6-phenylbutyl or tert-butyl and the rings A and B are unsubsti- 4H-s-t riazol[4,3-a][ 1,4]benzodiazepine. tuted or substituted by one member selected from the 1 1. A compound according to claim 7, said comgroup consisting of n-i tro. trifluoromethyl, chlorine, flu- '5 pound being 4-acetoxy-8-chloro-l-ethyl-6-phenyl-4H- orine. bromine, iodine, methyl; ethyl; propyl, methoxy s'-t'riazolo[4,3-a 1,4]bnzodiazepine.

and ethoxy. 1'2..A compound according to claim '7, said com- 9. A compound according to claim 7, said compound pound being 4-acetoxy 8-nitro-6-phenyl-4H-s-triazolobeing 4-acetoxy-8-chloro-6-phenyl-4H-s-triazolo-[4,3- [4,3-a][ l ,4]benzodiazepine. Y a][1,4]benzodiazepine. l0 f 

1. A MEMBER SELECTED FROM THE GROUP CONSISTNIG OF A COMPOUND OF THE FORMULA
 2. A compound according to claim 1, said compound being 8-chloro-4-hydroxy-6-phenyl-4H-s-triazolo-(4,3-a)(1, 4)benzodiazepine.
 3. A compound according to claim 1, said compound being 8-chloro-4-hydroxy-1-methyl-6-phenyl-4H-s-triazolo(4,3-a)(1, 4)benzodiazepine.
 4. A compound according to claim 1, said compound being 8-chloro-1-ethyl-4-hydroxy-6-phenyl-4H-s-triazolo(4,3-a)(1, 4benzodiazepine.
 5. A compound according to claim 1, said compound being 4-hydroxy-8-nitro-6-phenyl-4H-s-triazolo-(4,3-a)(1, 4)benzodiazepine.
 6. A compound according to claim 1, said compound being 8-chloro-4-methoxy-6-phenyl-4H-s-triazolo-(4,3-a)(1, 4)benzodiazepine.
 7. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF A COMPOUND OF THE FORMULA
 8. A compound of the formula
 9. A compound according to claim 7, said compound being 4-acetoxy-8-chloro-6-phenyl-4H-s-triazolo-(4,3-a)(1, 4)benzodiazepinE.
 10. A compound according to claim 7, said compound being 4-acetoxy-8-chloro-1-methyl-6-phenyl-4H-s-triazolo(4,3-a)(1, 4)benzodiazepine.
 11. A compound according to claim 7, said compound being 4-acetoxy-8-chloro-1-ethyl-6-phenyl-4H-s-triazolo(4,3-a)(1, 4)benzodiazepine.
 12. A compound according to claim 7, said compound being 4-acetoxy-8-nitro-6-phenyl-4H-s-triazolo-(4,3-a)(1, 4)benzodiazepine. 